This R21, written in response to PA-03-082 (Innovation Grant Program for AIDS Vaccine Research), poses the hypothesis that the immunopathology associated with lentiviral infection is, at least in part, a distal manifestation of inflammation induced by Gag/anti-Gag immune complexes. This hypothesis is based on a comparative analysis of pathogenic and non-pathogenic lentiviral infections in non-human primates. Pathogenic infections result in high viral loads, vigorous T and B cell responses against viral epitopes, and immunopathology, including T cell activation, progressive changes in T cell phenotype and function, destruction of hematolymphoid microenvironments, and immunodeficiency. By contrast, these manifestations of immunopathology and immunodeficiency are not observed in non-pathogenic infections, even in the face of high viral loads. A remarkable - and, we hypothesize, critical - distinction between pathogenic and non-pathogenic infections is that antibody responses to the Gag p27 capsid protein, but not to other viral proteins, are weak to undetectable in the setting of nonpathogenic infections. Given the unique property of Gag polypeptides to oligomerize into higher ordered structures with repeating arrays of identical epitopes, antibodies against Gag may more readily generate immune complexes than antibodies against other viral proteins. We speculate that such Gag/anti-Gag immune complexes will be more likely to bind to follicular dendritic cells (FDCs) in lymphoid organs and to thereafter trigger a series of events leading, ultimately, to immunodeficiency and death. Reciprocally, disease progression may proceed more slowly, or not at all, in the absence of such complexes. Should this dichotomy be correct, vaccine-induced augmentation of anti-Gag antibody responses may not be desirable; instead, vaccine-induced inhibition of such responses may be the strategy of choice. The experiments of this proposal are designed to test this hypothesis directly in the African green monkey species sabeus (AGMsab), using a potent immunization strategy (an adenoviral vector encoding a secreted form of SIV.sab Gag p27) to induce anti-Gag p27 antibodies and to determine whether, in the setting of SIVagm.sab infection, Gag/anti-Gag immune complexes formed by such antibodies are associated with disease progression. The following Specific Aims will be pursued: 1. To characterize and to compare T and B cell immune responses in African green monkeys after either vaccination with a recombinant adenoviral vector encoding a secreted form of SIVagm Gag p27 or after experimental SIVagm infection 2. To evaluate the impact of high circulating levels of anti-Gag p27 antibodies on the pathogenicity of experimental SIVagm infection in African green monkeys. [unreadable] [unreadable]